DAURISMO is the first and only Hedgehog
pathway inhibitor approved for the treatment of AML
In a randomized Phase 2 trial, DAURISMO plus
low-dose chemotherapy significantly improved median overall
survival in patients who were not able to receive intensive
chemotherapy due to age or comorbidities – a difficult-to-treat
patient population
Pfizer Inc. (NYSE:PFE) today announced that the U.S. Food and
Drug Administration (FDA) approved DAURISMO™ (glasdegib), a
once-daily oral medicine, for the treatment of newly-diagnosed
acute myeloid leukemia (AML) in adult patients who are 75 years or
older or who have comorbidities that preclude use of intensive
induction chemotherapy. DAURISMO is taken in combination with
low-dose cytarabine (LDAC), a type of chemotherapy. DAURISMO has
not been studied in patients with severe renal impairment or
moderate-to-severe hepatic impairment.1
AML is a rapidly progressing bone marrow cancer with poor
survival rates compared to other leukemias.2 The standard of care
for people with AML is intensive chemotherapy; however, for many
elderly patients with AML, as well as those who have certain health
conditions prior to receiving their diagnosis, intensive treatment
is not an option.3 Historically, a majority of these individuals do
not receive treatment and face a poor prognosis.4
“As our second medicine approved in the last 14 months for
patients with acute myeloid leukemia, DAURISMO reinforces our
commitment to delivering new medicines to patients living with some
of the most difficult-to-treat cancers, especially those for which
there are limited treatment options available,” said Andy Schmeltz,
Global President, Pfizer Oncology. “We are proud to now offer these
patients for whom intensive chemotherapy is not an option a new
oral medicine, taken in combination with low-dose chemotherapy,
that may improve their chances of survival.”
DAURISMO is the first and only FDA-approved Hedgehog pathway
inhibitor for AML. The Hedgehog signaling pathway plays an
essential role in embryogenesis, the process by which human embryos
are developed. In adults, however, abnormal activation of this
pathway is thought to contribute to the development and persistence
of cancer stem cells. Preclinical studies have shown that
disruption of this pathway can impair the development and survival
of these cancer stem cells.5,6
“The randomized Phase 2 study, which formed the basis for
today’s approval, included patients with cardiac disease or mild to
moderate kidney disease, who are often excluded from clinical
trials,” said Jorge Cortes, M.D., deputy chair and professor of
medicine in the Department of Leukemia, University of Texas, MD
Anderson Cancer Center. “In the trial, DAURISMO plus low-dose
chemotherapy reduced the risk of death during the study period by
54 percent compared to chemotherapy alone. This provides a
much-needed treatment for those patients for whom intensive
chemotherapy is not an option.”
In the pivotal, randomized, international Phase 2 BRIGHT 1003
trial, 115 patients with newly diagnosed AML were randomized 2:1 to
receive DAURISMO plus LDAC or LDAC alone. Of the 77 patients
treated with DAURISMO plus LDAC, more than half (51%, 39 patients)
had secondary AML, or AML that develops as a result of prior
blood/bone marrow conditions or previous anticancer therapy. Eleven
of the 39 patients with secondary AML received prior treatment with
a hypomethylating agent; historically, the prognosis is poor for
these patients and treatment options have been limited to clinical
trials or palliative care. Median overall survival was 8.3 months
(95% CI: 4.4,12.2) for patients treated with DAURISMO plus LDAC
compared with 4.3 months (95% CI: 1.9, 5.7) for patients treated
with LDAC alone. This difference represented a 54 percent reduction
in the risk of death for patients treated with DAURISMO plus LDAC
(HR: 0.46, 95% CI: 0.30, 0.71, one-sided p-value 0.0002).1
The U.S. labeling for DAURISMO includes a boxed warning for
embryo-fetal toxicity. The most frequently (≥20% of patients)
reported adverse events (AEs) in patients treated with DAURISMO
plus LDAC compared to LDAC alone in first 90 days of therapy were
anemia (43% vs 42%), fatigue (36% vs 32%), hemorrhage (36% vs 42%),
febrile neutropenia (31% vs 22%), musculoskeletal pain (30% vs
17%), nausea (29% vs 12%), edema (30% vs 20%), thrombocytopenia
(30% vs 27%), dyspnea (23% vs 24%), decreased appetite (21% vs 7%),
dysgeusia (21% vs 2%), mucositis (21% vs 12%), constipation (20% vs
12%) and rash (20% vs 7%).1 Serious adverse reactions were reported
in 79% of patients treated in the DAURISMO plus LDAC arm. The most
common (≥5%) serious adverse reactions in patients receiving
DAURISMO plus LDAC were febrile neutropenia (29%), pneumonia (23%),
hemorrhage (12%), anemia (7%) and sepsis (7%).1
“DAURISMO, a Hedgehog pathway inhibitor, was discovered in
Pfizer laboratories and exemplifies our continued commitment to
developing medicines that have the potential to advance cancer
therapeutics,” said Mace Rothenberg, M.D., Chief Development
Officer, Oncology, Pfizer Global Product Development. “We are
delighted by today’s approval of DAURISMO by the FDA, and are
working to gain greater understanding of its role in treating
patients with acute myeloid leukemia. The ongoing Phase 3 BRIGHT
trials are evaluating DAURISMO in combination with other agents
commonly used to treat patients with acute myeloid leukemia, in an
effort to understand the full potential of this medicine against
this aggressive leukemia.”
Pfizer is committed to ensuring that patients who are prescribed
DAURISMO have access to this innovative therapy. Patients in the
U.S. have access to Pfizer Oncology Together™, which offers
personalized support and financial assistance resources to help
patients access their prescribed Pfizer Oncology medications.
The full Prescribing Information, including BOXED WARNING, for
DAURISMO can be found here.
IMPORTANT DAURISMO SAFETY INFORMATION FROM THE U.S.
PRESCRIBING INFORMATION
WARNING: EMBRYO-FETAL TOXICITY: DAURISMO can cause
embryo-fetal death or severe birth defects when administered to a
pregnant woman. DAURISMO is embryotoxic, fetotoxic, and teratogenic
in animals. Conduct pregnancy testing in females of reproductive
potential prior to initiation of DAURISMO treatment. Advise females
of reproductive potential to use effective contraception during
treatment with DAURISMO and for at least 30 days after the last
dose. Advise males of the potential risk of DAURISMO exposure
through semen and to use condoms with a pregnant partner or a
female partner of reproductive potential during treatment with
DAURISMO and for at least 30 days after the last dose to avoid
potential drug exposure.
Blood Donation: Advise patients not to donate blood or
blood products while taking DAURISMO and for at least 30 days after
the last dose, because their blood or blood products might be given
to a female of reproductive potential.
QTc Interval Prolongation: Patients treated with DAURISMO
can develop QTc prolongation and ventricular arrhythmias, including
ventricular fibrillation and ventricular tachycardia. Monitor
electrocardiograms (ECGs) and electrolytes. Concomitant use of
DAURISMO with drugs known to prolong the QTc interval and CYP3A4
inhibitors may increase the risk of QTc interval prolongation. In
patients with congenital long QT syndrome, congestive heart
failure, electrolyte abnormalities, or those who are taking
medications known to prolong the QTc interval, more frequent ECG
monitoring is recommended. Interrupt DAURISMO if QTc interval is
>500 ms and discontinue permanently for patients who develop QTc
interval prolongation with signs or symptoms of life-threatening
arrhythmia.
Adverse Reactions: Most common adverse reactions
(incidence ≥20%) are anemia, fatigue, hemorrhage, febrile
neutropenia, musculoskeletal pain, nausea, edema, thrombocytopenia,
dyspnea, decreased appetite, dysgeusia, mucositis, constipation,
and rash.
Drug Interactions: Co-administration with strong CYP3A4
inhibitors increased DAURISMO plasma concentrations, which may
increase the risk of adverse reactions including QTc interval
prolongation. Consider alternative therapies that are not strong
CYP3A4 inhibitors during treatment with DAURISMO and monitor
patients for increased risk of adverse reactions including QTc
interval prolongation. Strong CYP3A4 inducers should be avoided due
to decreased DAURISMO plasma concentrations, which may reduce
efficacy.
Lactation: Because of the potential for serious adverse
reactions from DAURISMO in a breastfed child, advise women who are
taking DAURISMO not to breastfeed or provide breast milk to infants
or children during treatment and for at least 30 days after the
last dose.
About DAURISMO™ (glasdegib)
DAURISMO is a once-daily oral Hedgehog pathway inhibitor, taken
in combination with LDAC, for the treatment of newly diagnosed AML
in adult patients who are 75 years or older or who have
comorbidities that preclude use of intensive induction
chemotherapy.1 DAURISMO has not been studied in patients with
severe renal impairment or moderate-to-severe hepatic impairment.
As an oral therapy, which is taken with subcutaneous LDAC, DAURISMO
offers the flexibility for patients to receive this treatment
regimen at home or in the outpatient setting.
DAURISMO was discovered in Pfizer’s U.S. laboratories and we
utilize state-of-the-art continuous manufacturing to produce this
treatment.
DAURISMO is not approved for any indication in any market
outside the U.S.
About the BRIGHT Clinical Trials
BRIGHT AML 1019 (NCT03416179) consists of two randomized,
placebo-controlled Phase 3 trials evaluating the addition of
DAURISMO to intensive or non-intensive chemotherapy in patients
with newly diagnosed AML. In the first study, patients with AML
will be randomized to receive DAURISMO plus cytarabine and
daunorubicin, an intensive chemotherapy regimen, or placebo plus
cytarabine and daunorubicin. In the second study, patients with AML
for whom intensive chemotherapy is not an option will be randomized
to receive DAURISMO plus azacitidine, a hypomethylating agent, or
placebo plus azacitidine.
A separate Phase 1b BRIGHT 1012 study (NCT02367456) has also
been expanded to evaluate DAURISMO in combination with azacitidine
in patients with previously untreated high-risk myelodysplastic
syndromes (MDS) or AML. These trials are currently enrolling
patients.
About Pfizer Hematology
Pfizer’s commitment to hematologic malignancies began in 2012
with the approval of our treatment for chronic myeloid leukemia
(CML). Since then, we’ve continued to expand our hematology
portfolio to meet the needs of patients with acute lymphoblastic
leukemia (ALL) and AML. We now have four products approved for
leukemia in different countries around the world, including three
in the past two years. Together with the community, Pfizer aims to
overcome the challenges of hematologic cancers and translate
breakthrough science into meaningful treatment advances for
patients.
About Pfizer Oncology
At Pfizer Oncology, we are committed to advancing medicines
wherever we believe we can make a meaningful difference on the
lives of patients. Today, Pfizer Oncology has an industry-leading
portfolio of 14 approved cancer medicines across 22 indications,
including breast, prostate, kidney, lung and hematology. We also
have two oncology biosimilar medicines approved globally and
several assets in mid to late-stage development for the treatment
of cancer or as supportive care. Pfizer Oncology is striving to
change the trajectory of cancer.
Pfizer Inc.: Working together for a healthier world®
At Pfizer, we apply science and our global resources to bring
therapies to people that extend and significantly improve their
lives. We strive to set the standard for quality, safety and value
in the discovery, development and manufacture of health care
products. Our global portfolio includes medicines and vaccines as
well as many of the world's best-known consumer health care
products. Every day, Pfizer colleagues work across developed and
emerging markets to advance wellness, prevention, treatments and
cures that challenge the most feared diseases of our time.
Consistent with our responsibility as one of the world's premier
innovative biopharmaceutical companies, we collaborate with health
care providers, governments and local communities to support and
expand access to reliable, affordable health care around the world.
For more than 150 years, we have worked to make a difference for
all who rely on us. We routinely post information that may be
important to investors on our website at www.pfizer.com. In
addition, to learn more, please visit us on www.pfizer.com and
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@Pfizer and @Pfizer_News, LinkedIn, YouTube, and
like us on Facebook at Facebook.com/Pfizer.
DISCLOSURE NOTICE: The information contained in this release is
as of November 21, 2018. Pfizer assumes no obligation to update
forward-looking statements contained in this release as the result
of new information or future events or developments.
This release contains forward-looking information about DAURISMO
(glasdegib) and Pfizer Oncology, including their potential
benefits, that involves substantial risks and uncertainties that
could cause actual results to differ materially from those
expressed or implied by such statements. Risks and uncertainties
include, among other things, uncertainties regarding the commercial
success of DAURISMO; the uncertainties inherent in research and
development, including the ability to meet anticipated clinical
trial commencement and completion dates and regulatory submission
dates, as well as the possibility of unfavorable clinical trial
results, including unfavorable new clinical data and additional
analyses of existing clinical data; the risk that clinical trial
data are subject to differing interpretations, and, even when we
view data as sufficient to support the safety and/or effectiveness
of a product candidate, regulatory authorities may not share our
views and may require additional data or may deny approval
altogether; whether regulatory authorities will be satisfied with
the design of and results from our clinical studies; whether and
when drug applications may be filed in any other jurisdictions for
DAURISMO, for any additional indications for DAURISMO or for any
other oncology products; whether and when any such applications may
be approved by regulatory authorities, which will depend on the
assessment by such regulatory authorities of the benefit-risk
profile suggested by the totality the efficacy and safety
information submitted, and, if approved, whether DAURISMO or any
such other oncology products will be commercially successful;
decisions by regulatory authorities regarding labeling and other
matters that could affect the availability or commercial potential
of DAURISMO or any other oncology products; and competitive
developments.
A further description of risks and uncertainties can be found in
Pfizer’s Annual Report on Form 10-K for the fiscal year ended
December 31, 2017 and in its subsequent reports on Form 10-Q,
including in the sections thereof captioned “Risk Factors” and
“Forward-Looking Information and Factors That May Affect Future
Results”, as well as in its subsequent reports on Form 8-K, all of
which are filed with the U.S. Securities and Exchange Commission
and available at www.sec.gov and www.pfizer.com.
___________________________
1 DAURISMOTM (glasdegib) Prescribing
Information. New York. NY: Pfizer Inc: 2018.
2 SEER Cancer Stat Facts: Acute Myeloid
Leukemia. National Cancer Institute. Bethesda, MD, April 2017.
Available at: http://seer.cancer.gov/statfacts/html/amyl.html.
Accessed November 7, 2018.
3 Dohner H, Estey E, Grimwade D, et al.
Diagnosis and management of AML in adults: 2017 ELN recommendations
from an international expert panel. Blood. 2017;129:424-447.
4 Medeiros BC, Satram-Hoang S, Hurst D,
Hoang KQ, Momin F, Reyes C. Big data analysis of treatment patterns
and outcomes among elderly acute myeloid leukemia patients in the
United States. Ann Hematol. 2015;94:1127-1138.
doi:10.1007/s00277-015-2351-x.
5 Irvine DA, Copland M. Targeting hedgehog
in hematologic malignancy. Blood. 2012;119(10):2196-2204.
doi:10.1182/blood-2011-10-383752.
6 Laranjeira ABA, Yang SX. Therapeutic
target discovery and drug development in cancer stem cells for
leukemia and lymphoma: from bench to the clinic. Expert Opinion on
Drug Discovery. 2016;11(11):1071-1080.
doi:10.1080/17460441.2016.1236785.
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version on businesswire.com: https://www.businesswire.com/news/home/20181121005526/en/
Pfizer Media Contact:Jessica Smith,
212-733-6213Jessica.M.Smith@pfizer.comorPfizer Investor
Contact:Ryan Crowe, 212-733-8160Ryan.Crowe@pfizer.com
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